The Role Of Midbrain Chloride Ion Dysregulation In Escalated Alcohol Consumption

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Doctor of Philosophy (PhD)
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5-HT2A receptor
Neuroscience and Neurobiology
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Kimmey, Blake

Alcohol use is a prominent contributor to global disease burden and a leading cause of preventable mortality. Long-term severe problem drinking is clinically diagnosed as alcohol use disorder (AUD), one of the most prevalent neuropsychiatric diseases worldwide. Despite the persistent public health concern posed by alcohol abuse, treatments targeting specific brain mechanisms impacted by and driving pathological alcohol use are lacking. Behavioral animal models have revealed that the mesolimbic dopamine reward pathway is a critical mediator of alcohol’s reinforcing effects. The ventral tegmental area (VTA) is a central hub of this reward circuitry and subversion of alcohol-induced neuronal activity in the VTA has been linked to increased alcohol consumption. Among its many effects in the brain, alcohol enhances release of the inhibitory neurotransmitter GABA in the VTA. This acute effect of alcohol is exacerbated by prior alcohol, drug, or stress exposure, which are all risk factors for subsequent alcohol abuse. For these reasons, the central hypothesis of this dissertation was that disruptions in alcohol-induced inhibitory GABA signaling in the VTA contribute to escalated alcohol consumption. To delineate the mechanisms of disturbed VTA inhibitory transmission that may lead to increased alcohol consumption, electrophysiological recordings, in vivo pharmacological manipulations, and alcohol self-administration paradigms were performed in rodents. The second and third chapters provide evidence that an acute stressor in adulthood or chronic nicotine exposure in adolescence promote subsequent alcohol self-administration behavior via chloride ion (Cl-) dysregulation in VTA GABA neurons. Normalizing Cl- homeostasis by intra-VTA pharmacological upregulation of the potassium-Cl- cotransporter KCC2 prevented the increased alcohol drinking phenotype observed after stress or nicotine. In the fourth and fifth chapters, rescue of disrupted Cl- homeostasis via serotonin 2A receptor (5-HT2AR) activation is demonstrated ex vivo and correlated with 5-HT2AR agonist-mediated reduction in heavy alcohol consumption. Collectively, this body of work suggests that dysregulation of VTA Cl- transport, dictated largely by KCC2 function, increases risk for alcohol abuse. Targeting this form of inhibitory plasticity represents a novel interventional approach for AUD. Therefore, future work is needed to identify clinically safe and efficacious pharmacotherapies to reverse disturbances in midbrain Cl- homeostasis in alcohol-dependent individuals.

John A. Dani
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